Many people use drugs, but not everyone becomes addicted. Why?
Anne-Noël Samaha, Université de Montréal
Part of the reason comes down to how you take a drug. Are you smoking, injecting, snorting or swallowing it? That dictates how much drug gets into the brain, how fast, and how often brain levels of drug rise and fall. These are pharmacokinetic variables, and they reflect how your body absorbs and distributes a drug.
For instance, if you smoke a joint, brain levels of cannabis will both rise and decline much faster than if you had eaten the same amount of cannabis in a brownie. And a rapid rise and fall in brain levels of a drug is more likely to lead to addiction. That is why a substance can lead to addiction in one form (like nicotine in cigarettes) but can treat addiction in another (like the nicotine patch).
I am a professor of pharmacology, and I have been studying the role of pharmacokinetics in addiction for years. Studying these variables can help us understand the brain changes that lead to addiction. And by identifying these changes, we might be able to design ways of reversing them.
How fast and how often a drug gets to your brain can predict addiction
Addiction happens when a drug causes brain changes that lead a person to seek and take drugs compulsively. For the most part, researchers tend to focus on how much of a drug it takes to cause these brain changes.
But in predicting the risk of addiction, how fast and how often drugs get to the brain can be more important than how much.
Researchers have used rats to investigate this issue, finding that both the speed with which a drug reaches the brain and how often brain levels rise and fall during intoxication have a huge influence on addiction.
One series of studies carried out in part in my laboratory shows that rats taking rapid injections of a drug (cocaine, in this instance) develop a stronger desire for it.
In these studies, rats voluntarily pressed a small lever to take intravenous injections of cocaine daily. For some rats, each dose was injected quickly, in five seconds. This brings cocaine to the brain about as fast as smoking it. For other rats, cocaine was injected over 90 seconds, which gets it to the brain about as fast as snorting.
Compared to the rats taking slower injections, the rats taking rapid injections developed an excessive desire to obtain cocaine. After a long abstinence period, they were also more likely to resume pressing on the cocaine lever when given an opportunity to do so, which mimics relapse after abstinence. Importantly, differences between the two groups of rats were seen even when they had taken the same total number of drug injections.
Why are cigarettes addictive, but not the nicotine patch?
Other studies on rats suggest that how often brain levels of a drug rise and fall can better predict addiction than how much drug is taken.
To investigate, researchers tested how intermittent drug use compares with continuous drug use. One group of rats took intravenous injections of cocaine intermittently each day. This produces spikes and dips in brain levels of the drug. Another group took cocaine pretty much continuously, which produces high and stable brain levels.
The continuous group consumed four to five times more cocaine each day than the intermittent group. But later, the intermittent group showed that compared to the continuous group, they were willing to press on the drug lever much more often to obtain even very small amounts of cocaine. In other words, the intermittent group was willing to “pay” much more to get the drug.
In this context, consider the cigarette smoker versus the person using nicotine skin patches. The puff-by-puff inhalation of cigarette smoke produces intermittent spikes in brain levels of nicotine. The patch produces continuous levels of nicotine. Smoking cigarettes can be addictive; using nicotine patches usually isn’t.
Pharmacokinetics change the effects drugs have on the brain
Drugs engage the same brain circuits as other rewards, such as food, water and sex. When we encounter rewards, groups of neurons release the neurotransmitter dopamine into areas of the brain like the nucleus accumbens, which is part of the brain’s reward circuit. Dopamine acts as a call to attention and action. It tells us “Something important has just happened. Stay near it, and pay attention to learn how to make it happen again.”
A dopamine spike makes the event that caused it seem attractive. When a drug like cocaine reaches the brain rapidly, as when it is smoked or injected rather than snorted, it produces a faster increase in dopamine levels in the nucleus accumbens. This can make the drug seem more desirable, and could be part of the reason that addiction is more likely when drug levels in the brain rise rapidly.
What does this mean for addiction?
The only surefire way to protect yourself from addiction is not to take drugs. But humans have experimented with drugs for hundreds of generations, and they will continue to do so because drugs activate the brain’s reward circuit.
The brain has protective mechanisms that regulate drug intake to minimize costs and maximize benefits. For example, alcohol can make you feel brave and allow you to interact with others with greater ease. This can be a benefit. But at the same time, alcohol activates bitter taste receptors and also makes you feel dizzy. You could override both of these defenses if you really wanted to, but both can also protect you from drinking too much.
Two recent events in our human history challenge these protective mechanisms: the availability of purer drugs and the use of direct routes of drug administration, like injection. These developments allow us to get drugs into our brains faster and in a more spiking pattern – both of which increase the risk of addiction.
Knowing this, we could manipulate pharmacokinetic variables to change how fast drug levels in the brain rise and fall, and transform the effects of drugs. Manipulating these variables could make some drugs become more addictive, but it could also make some drugs go from being addictive to actually being therapeutic.
We are already using some of these principles to treat addiction. Methadone is used to treat heroin addiction. Both drugs activate the brain’s reward circuit, but oral methadone produces slowly rising drug levels in the brain, which allows it to act as a medical treatment for heroin addiction.
At the moment, researchers are studying the possibility of using oral amphetamine to treat cocaine addiction. When amphetamine is taken orally, drug levels rise in a slow and stable way. The idea is that by producing a low level of activity in the brain’s reward circuit, oral amphetamine could reduce cocaine use.
Wherever these ideas lead us, the available evidence already suggests that if we as addiction researchers ignore pharmacokinetics, we do so at our peril.
Anne-Noël Samaha receives funding from the Canadian Institutes of Health Research, the Canada Foundation for Innovation, the National Sciences and Engineering Research Council and the Fonds de recherche du Québec - Santé.